We recently completed a doubled blind placebo controlled study in which recombinant glycoprotein D of herpes simplex virus types-2 (gD2) and glycoprotein B (gB2) were combined with an MF59 lipid emulsion adjuvant or the adjuvant alone and administered as a series of 4 intramuscular injections to 202 men and women experiencing proven frequently recurring genital HSV-2 disease. The vaccinations succeeded in significantly reducing the severity of the first episode of herpes following the first vaccine dose. The monthly rate of reccurrence was not significantly reduced by the vaccine. Given that the degree of efficacy was far less than desired, the work on this vaccine has terminated. During the past year we completed, analyzed, and presented the findings from a second Phase-III study in which approximately 550 adults were vaccinated. Subjects were enrolled in multiple centers and are the monogamous seronegative partners of people with proven HSV-2 infection. The objective of that trial was to test the recombinant vaccine for efficacy in preventing acquisition of genital herpes disease. The vaccine failed! Based upon this, further work with this vaccine was terminated. We have turned instead to exploration of animal model systems and technologies in which we are testing novel DNA-based vaccines for genital herpes. This has the advantage of inducing CTL responses. To optimize the responses, we have prepared expression cassettes for multiple HSV-2 structure and regulatory genes and lymphocyte co-stimulatory genes.